Catalytic Enantioselective Synthesis of α-Difunctionalized Cyclic Sulfones

As saturated heterocyclic building blocks become increasingly popular in medicinal chemistry and drug discovery programs, expansion of the synthetic toolkit to novel stereofunctionalized heterocycles is a priority. Herein, we report the development of a palladium-catalyzed decarboxylative asymmetric allylic alkylation reaction to access a broad range of enantioenriched α-difunctionalized 5- and 6-membered sulfones from easily accessible racemic starting materials. The allylic alkylation step was found to occur with high levels of enantioselectivity as a result of a palladium-mediated dynamic kinetic resolution of E/Z enolate intermediates. This methodology paves the way to hitherto unexplored stereodefined cyclic sulfones for medicinal chemistry applications.


■ INTRODUCTION
Heterocycles have been and remain to be fundamental building blocks of the majority of small molecule drugs. 1 In order to enhance the developability of lead compounds and examine previously untapped areas of chemical and biological space, saturated heterocycles are becoming increasingly important in medicinal chemistry. 2 In particular, new asymmetric synthetic methods are sought after to access novel stereofunctionalized heterocycles as high value motifs for drug discovery. 3 Saturated cyclic sulfones bearing a tetrasubstituted αsulfonyl stereogenic center are a principal motif of a number of biologically active compounds ( Figure 1). For example, 1 and 2 are a patented ATR kinase inhibitor for cancer chemotherapy 4 and a matrix metalloproteinase inhibitor as an anti-inflammatory agent, 5 respectively. Similarly, tazobactam (3) is a very common modified penicillin that is used in the clinic as a β-lactamase inhibitor to combat bacterial resistance, 6 whereas Waldmann and co-workers have discovered that spirocyclic 4 is a selective and potent Mycobacterium tuberculosis protein tyrosine phosphatase B inhibitor, where the R enantiomer of 4 (IC 50 0.32 mM) was found to be 10 times more active than (S)-4. 7 As such, the development of new enantioselective approaches to install tetrasubstituted αsulfonyl stereogenic centers is a pertinent area of research. 8 To date, only a handful of strategies have been reported for the construction of enantioenriched α-difunctionalized 5-membered sulfones, namely, diastereoselectively by using enantiopure starting materials, 9 or a chiral auxiliary, 10 enantioselectively by oxidation of 1,3-dithiolanes, 11 and cyclization of linear precursors by means of enantioselective organocatalysis, 12 metal catalysis, 13 and photocatalysis. 14 In addition, there is only one report of an enantioselective entry to α-difunctionalized 6-membered sulfones, 15 utilizing stereoselective oxidation of 1,3-dithianes. To the best of our knowledge, there are no enantioselective methods that would enable the direct αdifunctionalization of cyclic sulfones and construct a tetrasubstituted α-sulfonyl stereogenic center.
To install the α-sulfonyl stereocenter under mild, base-free conditions, we sought to explore the palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) reac-tion. 16 Since the first report of the palladium-catalyzed DAAA reaction of ketone enolates with prochiral allylic electrophiles, 17 this process has been most commonly used in the allylation of prochiral cyclic enolates, derived from allyl ester and allyl enol carbonate precursors 5 and 6, respectively (A, Scheme 1). 18 While the cyclic nature of the enolate intermediate typically affords high levels of stereocontrol in the construction of the quaternary stereocenter in 7, the situation is more complex in the allylic alkylation of acyclic enolates: as the geometry of the enolate has an impact on the stereoselectivity of the reaction, the enolate precursor 8 must have a defined alkene geometry to ensure high levels of enantioselectivity in the formation of 9. 19 If a mixture of geometrical isomers of allyl enol carbonate 10 is used or a linear allyl ester substrate 11 affords a mixture of E/Z enolates in situ following decarboxylation, 20 then only low levels of enantioselectivity would be expected to result in the formation of 9. Due to the challenges associated with the preparation of geometrically pure allyl enol carbonate starting materials 8, the palladium-catalyzed DAAA reaction of acyclic enolates is less common. Notwithstanding, Murakami and co-workers have been able to obtain 9 with high ee from linear precursors 11 due to coordinating effects in the transition state of alkylation, 21 whereas Stoltz and co-workers have observed an unusual palladium-mediated dynamic kinetic resolution (DKR) of E/Z enolate intermediates, 22 giving 9 with high ee from either allyl enol carbonate 10, irrespective of its alkene geometry, or β-carbonyl ester 11.
Alongside enolates, α-sulfonyl anions are also known to undergo palladium-and iridium-catalyzed asymmetric allylic alkylation, 23 but these processes focus primarily on the installation of an allylic, rather than α-sulfonyl, stereogenic center. Although Tunge and co-workers successfully developed a stereoretentive palladium-catalyzed decarboxylative allylation of sulfones to give tetrasubstituted α-sulfonyl stereocenters, the use of enantiopure starting materials was required. 24 To construct enantioenriched tetrasubstituted α-sulfonyl carbon centers from achiral or racemic starting materials, we developed the first palladium-catalyzed DAAA reaction that affords α-difunctionalized cyclic sulfones, namely, thietane 1,1dioxides 14, from racemic β-carbonyl sulfones 12. 25 Despite the implication of a mixture of E/Z enolates 13, this reaction was found to proceed with high levels of stereoselectivity owing to the aforementioned palladium-mediated DKR of enolates. Herein, we describe the development of the palladium-catalyzed DAAA reaction of racemic 5-and 6membered sulfones 15−17 in order to access enantioenriched α-difunctionalized sulfolanes 18, thiane 1,1-dioxides 19, and thiomorpholine 1,1-dioxides 20 without the need for preformed geometrically pure allyl enol carbonate starting materials.

■ RESULTS AND DISCUSSION
To investigate the palladium-catalyzed DAAA reaction in detail, three substrate classes were prepared in a divergent manner from the following cyclic sulfone scaffolds (Scheme 2): sulfolane (21), thiane 1, 1-dioxide (22), and N-Boc thiomorpholine 1,1-dioxide (23). Sulfones 21−23 were appended with an allyl ester moiety in 24−26 in good yields. The reaction of the enolate of 24−26 with either a chloroformate or an acid chloride afforded a range of racemic ester-and ketonesubstituted sulfone substrates 15−17. The optimization of the palladium-catalyzed DAAA reaction began with benzyl-ester-substituted sulfolane substrate 15a (Table 1). When the reactions were run in THF as the solvent at room temperature in the presence of a set of ligands L1−4, PHOX ligand L1 afforded 18a in a racemic form (entry 1), whereas Trost ligands L2 and L3 gave poorly selective reactions (entries 2 and 3). The best result was obtained with (S,S)-ANDEN phenyl Trost ligand L4 (entry 4), installing the tetrasubstituted α-stereogenic center in 18a with 74% ee. Lowering the reaction temperature led to a small increase in selectivity (entry 5). A solvent screen indicated that DMF and acetonitrile were not selective (entries 6 and 7), whereas other solvents, such as toluene (entry 8), ethereal ones (entries 9−11), and chlorinated ones (entries 12 and 13), gave much higher selectivity. The best enantioselectivity of 86% ee was obtained with 1,4-dioxane as the solvent (entry 14), and the reaction was found to go to completion within 2 h (entry 15). Given the high freezing point of 1,4-dioxane, an attempt to lower the temperature of the reaction in a mixture of 1,4dioxane with THF did not lead to an enhancement of ee.
Using the optimal reaction conditions, a range of ester-and ketone-substituted cyclic sulfones 15−17 were tested to investigate the scope of this methodology (Scheme 3). Starting with sulfolanes 15, phenyl-and p-methoxyphenyl esters 18b and 18c were isolated with high ee. In addition, an X-ray crystal structure of 18b confirmed the absolute stereochemical configuration of the newly formed tetrasubstituted center, 26 which is also in agreement with the stereochemical outcome of allylic alkylation of thietane 1,1-dioxides. 25 By extension, the sense of stereoinduction was assumed to be the same for the other cyclic sulfone products. Alkyl esters 18c−g were also obtained with high stereoselectivity, albeit the ee of the smaller methyl ester 18h was lower (69% ee). High selectivity was also maintained in the formation of esters 18i and 18j that are functionalized with a substituted allyl group. Surprisingly, ketone substrates 15k−u were found to be much less reactive than esters, necessitating a higher catalyst loading (5 mol % [Pd 2 (dba) 3 ] and 13 mol % L4), where the higher stability of ketone enolates may potentially result in lower nucleophilicity. Although the ee values of aryl ketone products 18k−m were lower, high enantioselectivity was observed in the formation of products bearing larger alkyl ketone substituents, including secondary alkyl ketones 18n−q and tert-butyl 18r. With decreasing steric hindrance, the selectivity was moderate for primary alkyl ketones 18s and 18t, and very low for small methyl ketone 18u. When the same reaction conditions were applied to thiane 1,1-dioxide substrates 16, ester-substituted products 19a−c were formed with moderate selectivity. However, the allylic alkylation of thiane 1,1-dioxides 16 bearing a ketone side chain was more selective, giving phenyl ketone 19d, p-substituted ketones 19e−h, and heteroaryl ketone product 19i in 76−90% ee. Secondary alkyl ketones 19j−l were also formed with high enantioselectivity. tert-Butyl ketone substrate 16m failed to give 19m due to steric bulk, whereas the much smaller methyl ketone in 19n gave a low ee. Finally, thiomorpholine 1,1-dioxide precursors 17 were found to be even less reactive than sulfolanes 15 and thiane 1,1dioxides 16, requiring a higher catalyst loading even for ester substrates. The selectivity trend was similar to that of thiane 1,1-dioxide products 19: the ee values of esters 20a and 20b were moderate, whereas aryl and alkyl ketone products 20c and 20d were formed with much improved selectivity.
Having observed enantioselective product formation despite the implication of exocyclic enolate intermediates in this DAAA reaction, the impact of the enolate geometry on both the magnitude and the sense of enantioinduction was studied (A, Scheme 4). Geometrically pure allyl enol carbonates (Z)-27 and (E)-27, each of which should give rise to a geometrically pure enolate intermediate immediately after decarboxylation, were subjected to the catalytic reaction conditions. 18q was isolated in 82% ee from (Z)-27 and 71% ee from (E)-27, comprising the R stereochemical configuration of the major enantiomer in both cases. By comparison, β-ketoester 15q also afforded (R)-18q as the major enantiomer in 88% ee. Given that the sense of stereoinduction is the same in all three cases, it is likely that the selectivity in the formation of (R)-18q arises from the selective alkylation of one of the two possible enolates in a dynamic kinetic resolution. For this to be the case, a fast interconversion of enolate intermediates needs to take place. As β-ketoester 15q afforded (R)-18q with an ee (88%) that is closer in magnitude to the ee of (R)-18q derived from (Z)-27 (82%) than the ee of (R)-18q derived from (E)-27 (71%), it is likely that the rate of alkylation of the Z-enolate is faster than that of the E-enolate. As such, the enantioselectivity of allylation is presumably determined both by the rate of enolate isomerization and the steric effects of the enolate substituent in the transition state structure. We then tested how closely the enolate nucleophile and the π-allylpalladium(II) electrophile are associated during the course of the reaction (B, Scheme 4). Using a mixture of ester 15b and deuterium-labeled [D]-15d in addition to the expected products 18b and [D]-18d, the formation of crossover compounds [D]-18b and 18d was also observed. The result of the reaction of ketone precursors 15k and [D]-15l was analogous: a mixture of all four products 18k, [D]-18l, [D]-18k, and 18l was isolated. In light of full crossover, the nucleophile−electrophile ion pair can readily separate at some stage of the mechanism. Finally, to ascertain Given the implication of a palladium-mediated E/Z enolate interconversion prior to alkylation, the latter argument seems more likely. The tightly bound nature of the palladium enolate suggests that crossover must occur prior to decarboxylation.
The proposed mechanism of the reaction begins with oxidative addition of the palladium(0) catalyst to allyl ester 15 (Scheme 5). The resulting intermediate 30 is likely to exist as a loosely bound ion pair between a carboxylate and a πallylpalladium(II) complex that can readily undergo crossover. Subsequent decarboxylation gives rise to a mixture of E-and Zenolates 31, which are tightly associated with the σallylpalladium(II) complex. A fast isomerization of (E)-31 and (Z)-31 then takes place, presumably via a carbon-bound palladium enolate tautomer, and preferential allylic alkylation of (Z)-31 over (E)-31 gives rise to enantioenriched product 18.

■ CONCLUSIONS
In conclusion, we have developed a palladium-catalyzed decarboxylative asymmetric allylic alkylation reaction of 5and 6-membered sulfones that paves the way for enantioenriched α-difunctionalized sulfolanes, thiane 1,1-dioxides, and thiomorpholine 1,1-dioxides. The success of this approach in achieving high levels of enantioselectivity relies on the dynamic kinetic resolution of E-and Z-enolate intermediates. This method, therefore, offers clear advantages in terms of operational simplicity in that readily accessible racemic allyl ester starting materials can be used without the requirement for the stereoselective synthesis of geometrically pure allyl enol carbonate substrates. What remains to be explored is whether the palladium-mediated dynamic kinetic resolution of acyclic enolates is more generally applicable in the stereoselective allylation of other heterocyclic and acyclic building blocks. This work is ongoing in our laboratory. ■ EXPERIMENTAL SECTION General Information. Oven-dried glassware was used for all reactions under an argon atmosphere. Dry solvents were obtained from commercial sources or an Innovative Technologies PureSolv solvent drying system. All reagents and solvents were used as supplied. Ligands L1−4 were obtained from commercial sources. Petrol refers to the fraction of petroleum that boils between 40 and 60°C. Aqueous solutions were saturated unless stated otherwise. Silica gel (40−63 μm particle size) was used for flash column chromatography. Thin-layer chromatography (TLC) was carried out using silica gel 60 F254 aluminum-backed plates. Ultraviolet irradiation (254 nm) and staining with potassium permanganate or acidic ammonium molybdate(VI) solutions as appropriate were used to visualize TLC plates. 1 H NMR spectra were obtained using either a Bruker AVANCE III 400 MHz spectrometer or a Bruker FOURIER 300 MHz spectrometer, in CDCl 3 or DMSO-d 6 . 13 C NMR spectra were recorded on the same spectrometers at 100 or 75 MHz, respectively. For 1 H NMR spectra in CDCl 3 or DMSO-d 6 , the residual protic solvent CHCl 3 (δ H = 7.26 ppm) or the central resonance of the residual protic solvent DMSO-d 5 (δ H = 2.50 ppm), respectively, was used as the internal reference. For 13 C NMR spectra in CDCl 3 or DMSO-d 6 , the central resonance of CDCl 3 (δ C = 77.0 ppm) or DMSO-d 6 (δ C = 39.5 ppm), respectively, was used as the internal reference. Where rotamers were present, NMR data were recorded in DMSO-d 6 at 130°C. NMR data are reported as follows: chemical shift, δ H (in parts per million, ppm), (multiplicity, coupling constant, J in Hertz, and number of protons). Couplings are expressed as one, or a combination of the following: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; hept, heptet; and m, multiplet.
When coincidental coupling constants were observed in the NMR spectra, the apparent multiplicity of the proton resonance in these cases was reported. 1D nuclear Overhauser effect spectroscopy was used to determine the alkene geometry in (Z)-27 and (E)-27. Highresolution mass spectra (HRMS) were recorded using a Shimadzu LCMS-IT-TOF instrument using ESI or APCI conditions. Infrared spectra were recorded on an Agilent Technologies Cary 630 FTIR spectrometer. Melting points were measured on a Sanyo Gallenkamp capillary melting point apparatus. Enantiomeric excesses were determined by chiral HPLC on a Shimadzu NEXERA X2 UHPLC instrument equipped with a UV detector, using either a Chiralcel OD-H or Chiralpak AD-H column. Optical rotations were measured in CHCl 3 using an AA-65 Automatic Polarimeter.